In an article published in the September 2016 issue of Nature Genetics, scientists reported the genomic landscape of the Mediterranean basin and the greater Middle East, a central hub of ancient civilizations and home to approximately 10 percent of the world’s population. Project results provide important insights into two major areas in human genetics, namely the elucidation of the human migration pathways from Africa to Asia and Europe, and the identification of disease-associated genes. High consanguinity rates, a characteristic of Middle Eastern populations, enhance gene identification by four- to sevenfold.
The project was first proposed by Prof. Tayfun Özçelik of the Department of Molecular Biology and Genetics and an international group of scientists who convened at Bilkent University in 2009 and 2010. It was conducted over a period of five years, with a budget of tens of millions of dollars. More than 180 scientists from Algeria, Egypt, France, Israel, Iran, Iraq, Jordan, Lebanon, Libya, Morocco, Pakistan, Qatar, Saudi Arabia, Syria, Tunisia, Turkey, the United Arab Emirates and the United States contributed to the investigation. The Rockefeller University, Harvard University, MIT, the University of California, Cornell University, INSERM, Alfaisal University and İstanbul University were among the partner institutions involved in the project.
The honor of presenting the results of the project to the scientific world was given to Prof. Özçelik, who authored a “news and views” article published in the same issue of Nature Genetics as the study results.
As a first step in the investigation, an international group of scientists, including 30 from Turkey, formed the Greater Middle East Variome Consortium and established a DNA bank of 1,111 individuals, whose genomes were sequenced. In order to shed light on past human migration pathways, researchers then compared the genetic structures of Middle Eastern populations with those of the 1,000 Genomes Project populations from Europe, Asia, Africa, Australia and America.
The investigators found significant differences among the Middle Eastern populations, which are spread over a large geographic region from Northwest Africa to Southwest Asia. For instance, they discovered clusters of genomic regions that have resemblances to Asian or European populations. Patterns of human migration and drift were recapitulated, following a route out of Africa to Mesopotamia and Anatolia, from there to the Arabian Peninsula, Iran and Pakistan, and then on to India and across oceanic islands all the way to Australia. This journey covered a period of over 100,000 years.
Concurrently, important insights into the genetic diversity of Anatolian populations were documented; a flow of humans from Anatolia to Europe was also indicated. Historic evidence points to the central importance of Göbeklitepe and the present-day Urfa, Mardin and Gaziantep regions in the spread of ancient civilizations. The intergenetic distances between Northwest Africa and the Arabian Peninsula, or between Iran and Pakistan, were found to be significant (as are, for example, the differences between Finland and Tuscany); the highest levels of European admixture were observed for the Turkish peninsula, followed by the Syrian desert.
The other main focus of the project concerned identification of the genetic bases of inherited diseases. With the increasing scientific importance of genome projects over the past two decades, identification of disease-associated genes and development of diagnostic tests and targeted treatment modalities have become the basis of “precision medicine” initiatives.
In this context, the family structure of populations has become all the more relevant to understanding the human genomic landscape. More specifically, the presence of large families with many children and consanguinity between parents in the extended kindred facilitates the ability to distinguish normal genomic diversity from disease-causing mutations. For example, homozygosity blocks of over four megabases, a hallmark of disease-associated genetic changes, are observed exclusively in the Anatolian, Mesopotamian and Middle Eastern populations.
This offers a unique opportunity to fully exploit the potential of advanced, technology-driven genome interrogations to mitigate the burden of genetic disease on humanity. The large, consanguineous families to be found in Anatolia facilitate the identification of faulty genes by four- to sevenfold; in other words, it becomes as much 700 percent more likely that such genes may be identified in the population of the Anatolian peninsula than in that of America, Europe or China.
Genomics has been spectacularly successful in the identification of rare diseases such as cystic fibrosis, phenylketonuria, ataxia and inborn errors of metabolism. While rare diseases are, as the term indicates, individually rare, together they constitute the largest group of disorders—now totaling more than 5,000—that affect children in the developed world. In adults, however, rare diseases are eclipsed in incidence by complex disorders such as obesity, hypertension, diabetes, migraine, sleep problems, neurodegeneration and certain types of cancers.
Unfortunately, the genetic mutations that ultimately lead to these complex diseases remain by and large unknown. Scientists recognize that the main bottleneck is not due to technological constraints, but rather occurs at the conceptual level; thus, it is necessary to develop new strategies to interpret the sequences that constitute a genome. The Nature Genetics news and views article by Dr. Özçelik and his postdoctoral fellow Dr. Emre Onat presents a new conceptual framework and an analysis path for deciphering the molecular bases of complex diseases. The duo propose that the strategy used to identify the genes associated with Uner Tan syndrome, first described in quadrupedal families from Turkey a decade ago, and more recently the gene that leads to essential tremors and Parkinson’s disease, all identified at Bilkent, could be extended to a plethora of complex phenotypes.